This invention relates to the fields of pharmaceutical and organic chemistry and provides 2-arylbenzo[b]thiophenes which are useful for the inhibition of the various estrogen deficient conditions.
xe2x80x9cEstrogen deprivation syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have insufficient levels of the hormone estrogen. The most common cause of estrogen deprivation in women is the natural cessation of menses with age, i.e., menopause. Additionally, non-natural circumstances including surgical ovariectomy, chemotherapy causing the cessation of hormone production or pharmacologic action, and the like, may induce estrogen deprivation. Although numerous pathologies are contemplated by the use of this term, two major effects of estrogen deprivation syndrome are the source of the greatest long-term medical concern: osteoporosis and cardiovascular effects, especially hyperlipidemia.
Osteoporosis describes a group of diseases which arise from diverse etiologies, but are all characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass is the failure of the skeleton to provide adequate structural support for the body i.e. bone fracture. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an overall increase of the bone resorption and bone formation cycle where the resorptive cycle is more dominant. The obvious result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is attributed to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis.
Throughout pre-menopausal time, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
Although estrogen replacement therapy is often prescribed for the estrogen deprivation syndrome, it suffers from poor patient compliance as many women object to some of the side-effects and the inconvenience of the pharmaceutical forms of the medication. For example, 17-xcex2-estradiol is often administered via a transdermal patch, due to its poor oral absorption. As a result, a majority of women cease taking estrogen within the first year of beginning estrogen replacement therapy.
Compounds of formula I: 
where:
R and R1 are independently hydrogen, hydroxy, C1-C6 alkoxy, OCH2Ar, OCO(C1-C6 alkyl), OCOAr; and
Ar is phenyl or substituted phenyl;
are known as chemical intermediates to oral pharmaceutical agents, e.g. raloxifene hydrochloride.
The present invention concerns the discovery of utilities newly attributed to compounds of formula I, namely, that they are agents useful in inhibiting estrogen deprivation syndrome.
The current invention provides methods for inhibiting estrogen deprivation syndrome in mammals which includes administering to a mammal in need thereof an effective amount of a compound of formula I: 
where:
R and R1 are independently hydrogen, hydroxy, C1-C6 alkoxy, OCH2Ar, OCO(C1-C6 alkyl), OCOAr; and
Ar is phenyl or substituted phenyl; or
a solvate thereof.
Additionally, the current invention provides methods for inhibiting estrogen deprivation syndrome which includes administering to a mammal in need thereof an effective amount of a compound of formula I and a compound of formula II: 
where:
R2 and R3 are independently hydrogen, C1-C6 alkyl, CO(C1-C6 alkyl), or COAr;
R4 is pyrolidin-1-yl, piperidin-1-yl, or hexamethyleneimin-1-yl;
where the nitrogen of the R4 group is optionally the N-oxide; or
a pharmaceutical salt or solvate thereof.
Furthermore, the present invention concerns pharmaceutical formulations, comprising a compound of formula I, or compounds of formula I and II, and pharmaceutical excipients, diluents, or carriers.
General terms used in the description of compounds, methods, and formulations herein bear their usual meanings. For example, xe2x80x9cC1-C4 alkylxe2x80x9d refers to methyl, ethyl, propyl, iso-propyl, cyclopropyl, n-butyl, s-butyl, t-butyl, and cyclobutyl. The term xe2x80x9cC1-C6 alkylxe2x80x9d encompasses those listed for C1-C4 alkyl in addition to monovalent, straight, branched, or cyclic aliphatic chains of 5 or 6 carbon atoms including pentyl, cyclopentyl, hexyl, 2-methyl pentyl, cyclohexyl, and the like. The term xe2x80x9cC1-C4 alkoxyxe2x80x9d refers to methoxy, ethoxy, n-propoxy, iso-propoxy, cyclopropoxy, n-butoxy, s-butoxy, t-butoxy, and cyclobutoxy. The term xe2x80x9cC1-C6 alkoxyxe2x80x9d encompasses those listed for C1-C4 alkoxy in addition to straight, branched, or cyclic aliphatic chains of 5 or 6 carbon atoms which are attached through a monovalent oxygen atom and include but are not limited to, pentoxy, cyclopentoxy, hexoxy, 2-methylpentoxy, cyclohexoxy, and the like.
The term xe2x80x9chalidexe2x80x9d refers to chloride, bromide, or iodide.
The term xe2x80x9csubstituted phenylxe2x80x9d refers to a phenyl group having one to three substituents selected from the group consisting of C1-C6 alkyl, C1-C4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl.
Although the free-base form of formula II compounds can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutical salt form. Typical pharmaceutical salts include those salts prepared by reaction of the compounds of formula II with a mineral or organic acid. Such salts are known as acid addition salts. Thus, the term xe2x80x9cpharmaceutical saltxe2x80x9d refers to acid addition salts of a compound of formula II which are substantially non-toxic at the doses administered and are commonly known in the pharmaceutical literature. See e.g. Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66, 1, 1977. The pharmaceutical salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable for use in pharmaceutical formulations.
Examples of pharmaceutical salts are the iodide, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, g-hydroxybutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, hexyne-1,6-dioate, caproate, caprylate, chloride, cinnamate, citrate, decanoate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, propanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like of a compound of formula II.
The term xe2x80x9csolvatexe2x80x9d represents an aggregate that comprises one or more molecules of the solute, such as a compound of formula I or II, with one or more molecules of solvent. Such solvent molecules would be those commonly used in the pharmaceutical literature, which are known to be non-detrimental to the recipient, e.g., water and ethanol.
The term xe2x80x9cthermodynamic basexe2x80x9d refers to a base which provides a reversible deprotonation of an acidic substrate, or is employed as a proton trap when a proton is a byproduct of a reaction, and is reactive enough to effect the desired reaction without significantly effecting any undesired reactions. Examples of thermodynamic bases include, but are not limited to, carbonates, bicarbonates, and hydroxides (e.g. lithium, sodium, or potassium carbonate, bicarbonate, or hydroxide), tri-(C1-C4 alkyl)amines, or aromatic nitrogen containing heterocycles (e.g. pyridine).
The term xe2x80x9cestrogen deprivation syndromexe2x80x9d contemplates those pathologies and conditions brought about by the loss of ovarian function (either natural, surgically, or chemically induced) and specifically to the loss of the ovarian hormones, especially estrogen. Since loss of estrogen is causative for the symptoms of the syndrome, each of those symptoms responds to the replacement of the lost estrogen hormone through the administration of the compounds of the current invention. Thus, the compounds and methods of the current invention would be useful and beneficial in treating or preventing estrogen deficiency symptoms, which include but are not limited to the following: osteoporosis, hyperlipidemia, atherosclerosis, vasomotor abnormalities (hot flashes), auto-immune diseases, skin and hair abnormalities, cardio-vascular disease and degeneration, dementia and Alzheimer""s disease, depression, weight gain or loss, certain types and conditions of diabetes, inappropriate healing and tissue repair, vaginal atrophy, urinary incontinence, sequelae of abnormal regulation of estrogen controlled genes, intra alia. It should be recognized that not all patients being treated for estrogen deprivation syndrome symptoms will necessarily have all the various pathologies listed, supra, thus, the specific use of the compounds and methods of the current invention may vary depending on the idiosyncratic nature and severity of those symptoms.
The terms xe2x80x9cinhibitxe2x80x9d or xe2x80x9cinhibitingxe2x80x9d mean prohibiting, treating, alleviating, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of a pathological symptom related to or resultant from estrogen deprivation syndrome. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate.
As used herein, the term xe2x80x9ceffective amountxe2x80x9d means an amount of compound or compounds of the present invention which is capable of inhibiting the symptoms of the various pathological conditions and symptoms, herein described.
By xe2x80x9cpharmaceutical formulation,xe2x80x9d xe2x80x9cpharmaceutical carrier,xe2x80x9d xe2x80x9cpharmaceutical diluent,xe2x80x9d and xe2x80x9cpharmaceutical excipientxe2x80x9d it is meant that in a formulation containing a compound of formula I or a formulation containing a combination of a compound of formula I and II, the carrier, diluent, excipients, and salt are compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
While all of the compounds of the present invention are useful, certain of the compounds are particularly interesting and are preferred. For example, compounds of formula I where R and R1 are independently hydroxy or methoxy are preferred. The compound of formula I where R and R1 are both hydroxy, i.e. 2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene, is most preferred. In addition, the hydrochloride salt of the compound of formula II where R2 and R3 are both hydrogen, and R4 is piperidin-1-yl is also particularly preferred. This compound of formula II is [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride i.e. Raloxifene hydrochloride.
While all the formulations and methods employing a combination of a compound of formula I and II are useful, the possible combinations employing the preferred compounds listed above are particularly interesting and preferred. Most preferred is the combination of 2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene and Raloxifene hydrochloride.
The compounds of formula I may be prepared from compounds of formula III and IV as illustrated in Scheme 1 below where R and R1 are as described supra. 
Compounds of formula III may be S-alkylated with a phenacyl halide of formula IV. Such S-alkylations are carried out in a solvent in the presence of a thermodynamic base at temperatures between 0xc2x0 C. and 100xc2x0 C. for one to twenty-four hours. A preferred solvent and base are typically ethanol and potassium hydroxide respectively. The reaction is preferably performed at ambient temperature for one to three hours. A preferred halide for the compound of formula IV is bromide.
The resulting compounds of formula V are cyclized to the compounds of formula I by treatment with an acid in a suitable solvent at a temperature between 50xc2x0 C. and 200xc2x0 C. for one to twenty-four hours. A preferred solvent and acid is polyphosphoric acid.
When R and/or R1 is to be hydroxy, it is preferred that the above sequence be performed with a compound of formula III and/or IV where R and/or R1 is C1-C6 alkoxy, OCH2Ar, OCO(C1-C6 alkyl), or OCOAr. The compounds of formula I where R and/or R1 are hydroxy may then be prepared after the cyclization step by removing the C1-C6 alkyl, CH2Ar, CO(C1-C6 alkyl), or COAr moieties (protecting groups) from the resulting compounds of formula I. Methods for removing these protecting groups may be found in the Examples section which follows or in Chapter 2 of xe2x80x9cProtective Groups in Organic Synthesis, 2nd Edition, T. H. Greene, et al., John Wiley and Sons, New York, 1991.
Compounds of formula I where R and R1 are not hydrogen and only one of R or R1 is hydroxy, may be prepared from compounds of formula I where R and R1 are independently and differently C1-C6 alkoxy, OCH2Ar, OCO(C1-C6 alkyl), or OCOAr by removing selectively one of the protecting groups. Protecting groups which facilitate a selective removal and methods for the selective removal of one protecting group over the other are well known in the art. One example where selective removal is possible is where one protecting group is benzyl and the other is C1-C4 alkyl. The benzyl group may be removed selectively by catalytic hydrogenation. For further instruction on selective removal of these protecting groups see the Examples section which follows and the Greene reference cited above.
For further instruction on the preparation of compounds of formula I see U.S. Pat. Nos. 4,133,814 and 4,418,068 and the publication, Jones, C. D., et al., J. Med. Chem., 27, pp. 1057-1066 (1984), the teachings of which each are herein incorporated by reference.
The compounds of formula II which are not N-oxides, and their pharmaceutical salts, may also be prepared as taught in the previously incorporated U.S. Patents and also as taught in U.S. Pat. Nos. 5,393,763 and 5,629,425, and PCT publication Ser. No. 97/04259, the teachings of which each are herein incorporated by reference.
The compounds of formula II which are N-oxides may be prepared by dissolving or suspending a compound of formula II which is not an N-oxide in dilute aqueous solutions of hydrogen peroxide with a co-solvent such as methanol or ethanol. Reaction conditions for this reaction may range from ambient temperature to 100xc2x0 C. and in duration from 24 to 72 hours. It should be noted that care must be taken in selecting the oxidizing agent and that many commonly used agents, e.g., chromic anhydride, potassium permanganate, and the like, capable of oxidizing the nitrogen can not be used, since they would also oxidize the sulfur of the benzo[b]thiophene. Thus, a milder agent such as hydrogen peroxide is preferred.
The optimal time for performing the reactions described herein can be determined by monitoring the progress of the reaction via conventional chromatographic techniques. Furthermore, it is preferred to conduct the reactions of the invention under an inert atmosphere, such as, for example, argon, or, particularly, nitrogen. Choice of solvent is generally not critical so long as the solvent employed is inert to the ongoing reaction and sufficiently solubilizes the reactants to effect the desired reaction. Intermediate and final products may be purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or alumina.
Compounds of formula III and IV are either commercially available or may be prepared by methods well known in the art.
The discussion of the synthesis is not intended to be limiting to the scope of the present invention, and should not be so construed. Application of the above chemistry enables the synthesis of the compounds of formula I, which includes, but is not limited to:
2-phenylbenzo[b]thiophene;
2-(4-hydroxyphenyl)benzo[b]thiophene;
2-(4-methoxyphenyl)benzo[b]thiophene;
2-(4-acetoxyphenyl)benzo[b]thiophene;
2-(4-benzoyloxyphenyl)benzo[b]thiophene;
2-(4-isopropoxyphenyl)benzo[b]thiophene;
2-phenyl-6-hydroxybenzo[b]thiophene;
2-phenyl-6-methoxybenzo[b]thiophene;
2-phenyl-6-isopropoxybenzo[b]thiophene;
2-phenyl-6-acetoxybenzo[b]thiophene;
2-phenyl-6-(4-methylbenzoyl)oxybenzo[b]thiophene;
2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene;
2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene;
2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene;
2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene;
2-(4-isopropoxyphenyl)-6-methoxybenzo[b]thiophene;
2-(4-isopropoxyphenyl)-6-hydroxybenzo[b]thiophene;
2-(4-methoxyphenyl)-6-isopropoxybenzo[b]thiophene;
2-(4-hydroxyphenyl)-6-isopropoxybenzo[b]thiophene;
2-(4-acetoxyphenyl)-6-acetoxybenzo[b]thiophene;
2-(4-methoxyphenyl)-6-acetoxybenzo[b]thiophene;
2-(4-acetoxyphenyl)-6-methoxybenzo[b]thiophene;
2-(4-acetoxyphenyl)-6-hydroxybenzo[b]thiophene;
2-(4-hydroxyphenyl)-6-acetoxybenzo[b]thiophene;
2-(4-benzoyloxyphenyl)-6-hydroxybenzo[b]thiophene;
2-(4-benzoyloxyphenyl)-6-benzoyloxybenzo[b]thiophene;
2-(4-cyclopentoxyphenyl)-6-hydroxybenzo[b]thiophene;
2-(4-hydroxyphenyl)-6-cyclopentoxybenzo[b]thiophene;
2-(4-cyclopentoxyphenyl)-6-cyclopentoxybenzo[b]thiophene;
2-(4-butoyloxyphenyl)-6-hydroxybenzo[b]thiophene;
2-(4-cyclopentoxyphenyl)-6-acetoxybenzo[b]thiophene; and the like.
Formulations and methods employing both a compound of formula I and II include, but are not limited to, the following combinations of the two compounds:
2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone N-oxide;
2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone N-oxide;
2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-methoxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-acetoxyphenyl)-6-acetoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-cyclopentoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride;
2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone N-oxide;
2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone N-oxide; and the like.
The following Preparations and Examples further illustrate the synthesis of the compounds of the present invention. The examples are not intended to be limiting to the scope of the invention in any respect, and should not be so construed. The terms and abbreviations used in the instant preparations and examples have their normal meanings unless otherwise designated. For example xe2x80x9cxc2x0 C.xe2x80x9d, xe2x80x9cNxe2x80x9d, xe2x80x9cmmolxe2x80x9d, xe2x80x9cgxe2x80x9d, xe2x80x9cmLxe2x80x9d, xe2x80x9cMxe2x80x9d, xe2x80x9cHPLCxe2x80x9d, xe2x80x9cmpxe2x80x9d, xe2x80x9cEAxe2x80x9d, xe2x80x9cMSxe2x80x9d, and xe2x80x9c1H-NMRxe2x80x9d, refer to degrees Celsius, normal or normality, millimole or millimoles, gram or grams, milliliter or milliliters, molar or molarity, high performance liquid chromatography, melting point, elemental analysis, mass spectrum, and proton nuclear magnetic resonance respectively.
2-(3-Methoxyphenylthio)-4xe2x80x2-Methoxyacetophenone
3-Methoxythiophenol (50.0 g, 0.356 mol) was dissolved in 700 mL of ethanol. To this mixture was added (20 g, 0.36 mol) of potassium hydroxide pellets. A total of (82.5 g, 0.36 mol) of 2-bromo-4xe2x80x2-methoxyacetophenone was added in small portions to keep the temperature of the reaction at approximately 25xc2x0 C. The reaction was allowed to proceed at ambient temperature for three hours. The reaction was terminated by evaporation of the alcohol, which resulted in obtaining a brown oil. The oil was partitioned between 2 L of water and 1.5 L of diethylether. The ether layer was separated and washed with water, dried with anhydrous magnesium sulfate, and evaporated to a solid. The solid was crystallized from a mixture of diethylether-petroleum ether (3:1) to yield 78.5 g of the title compound as a pink crystalline solid. mp 53xc2x0 C.-54xc2x0 C. EA calculated for C16H16O3S: C, 66.64; H, 5.59; O, 16.64; S, 11.12. Found: C, 66.55; H, 5.87; O, 16.82; S, 10.86.
2-Phenylthioacetophenone
Thiophenol and 2-bromoacetophenone were converted to the title compound by the procedure of Preparation 1. mp 52xc2x0 C.-53xc2x0 C. EA calculated for C14H12OS: C, 73.65; H, 5.30; O, 7.01; S, 14.04. Found: C, 73.46; H, 5.50; O, 7.25; S, 14.30.
2-Phenylthio-4xe2x80x2-Methoxyacetophenone
Thiophenol and 2-bromo-4xe2x80x2-methoxyacetophenone were converted to the title compound by the procedure of Preparation 1. mp 83xc2x0 C.-85xc2x0 C. EA calculated for C15H14O2S: C, 69.74; H, 5.46. Found: C, 69.52; H, 5.48.
2-(3-Isopropoxyphenyl)-4xe2x80x2-Methoxyacetophenone
3-Isopropoxythiophenol and 2-bromo-4xe2x80x2-methoxyacetophenone were converted to the title compound by the procedure of Preparation 1.